Soluble Urokinase Plasminogen Activator Receptor Levels Are Associated with Severity of Fibrosis in Patients with Primary Sclerosing Cholangitis

Abstract

The soluble urokinase-type plasminogen activator receptor (suPAR) has evolved as a useful biomarker for different entities of chronic liver disease. However, its role in patients with primary sclerosing cholangitis (PSC) is obscure. We analyzed plasma levels of suPAR in 84 patients with PSC and compared them to 68 patients with inflammatory bowel disease (IBD) without PSC and to 40 healthy controls. Results are correlated with clinical records. suPAR concentrations were elevated in patients with PSC compared to patients with IBD only and to healthy controls (p < 0.001). Elevated suPAR levels were associated with the presence of liver cirrhosis (p < 0.001) and signs of portal hypertension (p < 0.001). suPAR revealed a high accuracy for the discrimination of the presence of liver cirrhosis comparable to previously validated noninvasive fibrosis markers (area under the curve (AUC) 0.802 (95%CI: 0.702−0.902)). Further, we demonstrated that suPAR levels may indicate the presence of acute cholangitis episodes (p < 0.001). Finally, despite the high proportion of PSC patients with IBD, presence of IBD and its disease activity did not influence circulating suPAR levels. suPAR represents a previously unrecognized biomarker for diagnosis and liver cirrhosis detection in patients with PSC. However, it does not appear to be confounded by intestinal inflammation in the context of IBD.

Keywords: biomarkers; liver cirrhosis; primary sclerosing cholangitis; soluble urokinase plasminogen activator receptor.

Figure 1

Plasma suPAR levels are elevated in patients with PSC. Circulating soluble urokinase-type plasminogen activator receptor (suPAR) levels are elevated in patients with PSC compared to healthy controls (p < 0.001). Box plots are displayed, where the bold line indicates the median per group, and the edges of the box are the first and third quartiles. The horizontal lines show minimum and maximum values of calculated nonoutlier values. The dots represent calculated outliners (A). Application of receiver operating characteristic (ROC) curve analyses to quantify the discriminatory power of suPAR revealed an area under the curve (AUC) of 0.728 (95% confidence interval (CI): 0.641–0.816) (B). Soluble urokinase-type plasminogen activator receptor (suPAR). Area under the curve (AUC). (*** p < 0.001).

Figure 2

suPAR is associated with the presence of liver cirrhosis. Soluble urokinase-type plasminogen activator receptor (suPAR) is elevated in patients with liver cirrhosis (p < 0.001) (A). suPAR is linked to an increasing Child–Pugh score (CHILD) in patients with liver cirrhosis (p = 0.019; A–C: p = 0.047; B–C: p = 0.046; A–B: n.s.) (B). In line with this, according to Spearman rank correlation, suPAR increases with increasing model of end-stage liver disease (MELD) score (p > 0.001; r = 0.547) (C). Subdivision of groups with different fibrosis stages revealed an elevation in suPAR levels (p = 0.017; F1 vs. F4 p = 0.001; F1–F2: n.s.; F1–F3: n.s.;F2–F3: n.s.) (D). suPAR revealed a high accuracy for the discrimination of the presence of liver cirrhosis (area under the curve (AUC) 0.802 (95%CI: 0.702–0.902), which is comparable to previously validated noninvasive fibrosis markers such as the fibrosis-4 (FIB4) index (AUC 0.836; 95%CI (0.752–0.920) and aspartate transaminase-to-platelets ratio index (APRI) score (AUC 0.866; 95%CI (0.789–0.944). The combination of suPAR and APRI score further improved the diagnostic power for the discrimination of the presence of liver cirrhosis (AUC 0.859 (95%CI (0.780–0.938)) (E). Subdivision of our cohort into patients with no to mild fibrosis (F0–F2) and patients with a higher degree of fibrosis (F3–F4) demonstrated a lower AUC of 0.771 (95%CI (0.669–0.874) for suPAR. However, the AUC was still comparable to the FIB4 index (AUC 0.812; 95%CI (0.720–0.905) and APRI score (AUC 0.844; 95%CI (0.754–0.935) (F). Box plots are displayed, where the bold line indicates the median per group and the edges of the box are the first and third quartiles. The horizontal lines show minimum and maximum values of calculated nonoutlier values. The dots represent calculated outliners. Soluble urokinase-type plasminogen activator receptor (suPAR). Child–Pugh Score (CHILD). Model of end-stage liver disease (MELD). Fibrosis-4 (FIB4) index. Aspartate transaminase-to-platelets ratio index (APRI). (* p < 0.05; *** p < 0.001).

Figure 3

suPAR levels indicate acute cholangitis but not the presence of a dominant stenosis. Our analysis revealed a significant elevation in soluble urokinase-type plasminogen activator receptor (suPAR) levels in patients with acute cholangitis episodes compared to patients without acute cholangitis (p < 0.001) (A). In line with this, Spearman rank correlation showed a positive correlation between circulating suPAR levels and CRP values (p < 0.001; r = 0.641) (B). However, circulating suPAR levels did not indicate the presence of dominant stenosis (C). Box plots are displayed, where the bold line indicates the median per group and the edges of the box are the first and third quartiles. The horizontal lines show minimum and maximum values of calculated nonoutlier values. The dots represent calculated outliners. Soluble urokinase-type plasminogen activator receptor (suPAR). (*** p < 0.001).

Figure 4

suPAR levels are not increased in patients with inflammatory bowel disease. Compared to healthy controls, soluble urokinase-type plasminogen activator receptor (suPAR) levels were elevated in patients with PSC (p < 0.001), but not in patients with inflammatory bowel disease (IBD) (A). Moreover, suPAR levels were independent of the presence of colitis ulcerosa (CU) and Crohn’s disease (CD) (B). suPAR levels did not differ depending on the IBD manifestation side (C), and they did not reflect the disease activity in patients with CU (D) and CD, respectively (E). Box plots are displayed, where the bold line indicates the median per group and the edges of the box are the first and third quartiles. The horizontal lines show minimum and maximum values of calculated nonoutlier values. The dots represent calculated outliners. Soluble urokinase-type plasminogen activator receptor (suPAR). Colitis ulcerosa (CU) and Crohn’s disease (CD). (*** p < 0.001).

Figure 5

suPAR levels correlate with CRP levels in patients with CD. Soluble urokinase-type plasminogen activator receptor (suPAR) levels correlated with C-reactive protein (CRP) in patients with Crohn’s disease (CD). Spearman rank correlation revealed a positive correlation between suPAR and CRP levels in patients with CD (p = 0.003; r = 0.473), but not in patients with ulcerative colitis (UC) (p = 0.096; r = 0.315) (A,B). Spearman rank correlation of suPAR and fecal calprotectin levels in patients with UC demonstrated no significant association; however, a tendency towards a significant positive correlation could be detected (p = 0.075; r = 0.619). In contrast, suPAR levels appeared to be independent of fecal calprotectin levels in patients with CD (p = 0.075; r = 0.619) and CU (p = 0.8; r = 0.078) (C,D). Soluble urokinase-type plasminogen activator receptor (suPAR). Gastrointestinal (GI). Colitis ulcerosa (CU). Crohn’s disease (CD). C-reactive protein (CRP).